3-(omega-hydrazino) alkylindoles



The alkyle sw-nYbnAziNmALxYLlNnonns l Richard A. Robinson, Fiv a nstom llh, assignor to G. D. Searle & Co., Chicago, 111;, a corporation pf Delaware No Drawing. Filed Apr. 28, 1959,;SerJNo-1 809,351 4Claims. or 2604319 i f The present invention relates to novel organic" bases 5 which are characterized by an indole ring structure and contain also a hydrazine group. These compounds are 3-(w-hydrazino)alkylindoles and can be represented by the structural formula l I mikona nunn (R4). a"

wherein Alk is an alkylene radical containing fewer than 6 carbon atoms; R is hydrogen or a lower alkyl radical; R is hydrogen or a hydrocarbon radical containing fewer 2,947,758 Ref e A e- 9? wherein R and R are .s elected from thegroup consisting 5 alkyl radical are preferably prepared from a 3-(2-oxoof hydrogen andlower alkyl radicals. A process for the manufacture of these compoundsinvolves the reaction of an indolemethyl carbonyl compound of the structuralformula H wherein R is hydrogen'or a lower alkyl group, "with a hydrazine of the structural formula v p wherein R is hydrogen or a lower alkylgroup; ,ina hydrogen atmosphere in the presence of a catalytic quantity' of platinum oxide. A suitable starting material for thepreparationof,compounds in whichflR is hydrogen, is 3-formylmethylindole. As a specific example, amixture .of the latter aldehyde, hydrazine, acetic acid, and platinum oxide is jreacted'in a hydrogen atmosphere to afford 3-(2-hydrazinoethyl)indole. On'the other hand, the aforementioned compounds in which R is a lower alkyl)indole in which'the alkyl. radical contains 3-10 carbon atoms. Forexample, 3-(2-oxopropyl.)indole and fisopropylhydrazine are reacted in ahydrogenatmosphere in the presence .of acetic acid. and platinum oxide, re-

than 8 carbon atoms and optionallysubstituted by an fsulting' in .3 (2-isopropylhydrazino12emethyl)ethylindole.

hydroxyl group; R is selected from the group consisting of hydrogen and benzyl and lower alkyl radicals; R ris selected fromthe group consisting of halogen and-hydroxyl, lower alkyl, loweralkox-y, and'lower alkanoyl radicals; and n is 0 or a positive integer less than 4.

Lower alkyl radicals asdefined herein are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and branched-chain isomers thereof. Lower alkoxy groups are defined as those possessing the structure 0-1 e. a yl while the term lower-aka structure.

ne radicals represented by Alk are fied by -CH (methylene) --OH2CH (ethylene) -CHiCHzGHz (trimethylene) CH2OH:CH2CHa- (tetramethylene) CH3 --CH1H (1,2-propylene) CH3 'CH2|CHCH2 (2-methyl-l,3-propylene) Examples of hydrocarbon radicals containing fewer than 8 carbon atoms and optionally substituted by an exempli- It is readily apparent that the compounds-in which R and .R are lower alkyl groups result from the-reaction. of 3-(2-oxoalkyl)indo1es with alkylhydrazines, both of which aredefined supra. .j

' v The compounds of the present-invention are .useful as result of their valuable pharmacological properties. They are, forexample, central'nervous systemstimulants. .-As

is known to those skilled in the art, substances ,of .this

type are effective in alleviating the symptomsassociated withdepressive states. 5 1 j W The invention will appear .more 'fully from the 'ex- ,amples whichJfOllow. These examples are set forth by way of, illustration only audit will be understood that the invention is notto be construed as limited in spirit or'fin scope by the details contained therein'jas' many i'modifications in materials and methods wilLbe apparent inthis disclosure to those skilled in'the art. In these examples temperatures are given in degrees centigrade C.). Pressures are designated as pounds per square inch (p.s.i.). Quantities of materials are expressed in parts by weight unless otherwise noted.

EXAMPLE 1 3- (Z-hykirazinoethyl) indole A mixture of 16 parts of 3-formylmethylindole, 6 parts of hydrazine hydrate, 7 parts of acetic acid, 0.25 part of platinum oxide, and 200 parts of methanol is shaken in a hydrogen atmosphere at 15 p.s.i. until one molecular equivalent of hydrogen is absorbed. The catalyst is rehydroxyl group, as represented by R2, are methyl, ethyl, moved by filtration and the filtrate concentrated to drybutyl, heptyl, cyclopentyl, cyclohexyl, 2-hydroxyethyl, 3- hydroxybutyl, phenyl, benzyl, tolyl, hydroxyphenyl, hydroxybenzyl, and trihydroxyphenyl.

Preferred embodiments of this invention are the 3- hydrazinoalkylindoles represented by the structural formula 0 washed with isopropanol to afford 3-(2-hydrazinoethyl)- 4 ness in vacuo. The residue is treated with dilute sodium hydroxide and ether, and the ether extract dried over anhydrous sodium sulfate. Evaporation of the ether in vacuo results in 3-(2-hydrazinoethy1)-indole.

By the addition of one molecular equivalent of oxalic acid to the aforementioned ether solution of the product, the oxalic acid salt is obtained. The precipitate is collected by filtration and extracted with water. The aqueous extract is evaporated to dryness and the residue indole oxalate.

By substituting n-butylhydrazine and otherwise pro- 3 ceeding according to the herein described processes, 3-[2- (n-butylhydrazino)ethyllindole is obtained.

7 EXAMPLEZ V .3-(Z-hydrazino-Zmwthyllelhylindo la A mixture of '34 parts of 3-(2-oxopropyl)indole, 12 parts of hydrazine hydrate, 14 parts of acetic acid, 0.5 part of platinum oxide, and 300 parts of methanol is shaken under hydrogen at 15 psi. until one molecular equivalent of hydrogen is absorbed. Removal of the catalyst by filtration and distillation of the solvent in vacuo results in a residue which is treated with dilute EXAMPLE 3 3-(2-oxo-n-pentyl)indole To a solution of 114 parts of methyl magnesium bromide in 600 parts of ether is added at 5 over a period of about one hour, a solution of 96 parts of indole in 180 parts of ether. Stirring at 05 is continued for about 45 minutes. A solution of 85 parts of 1,2-pentylene oxide in.400 parts of benzene is added dropwise and the resulting mixture allowed to react at 0 with stirring for two hours, then at room temperature for two hours. The solvents are distilled over a period .of about hours on the steam bath and the residue treated successively with cracked ice and solid carbon dioxide. Extraction .of this mixture with ether followed by evaporation of the ether alfords 3-(2-hydroxy-n-pentyl)-indole which distills at about 162/ 0.05 mm.

A mixture of 100 parts of 3-(2-hydroxy-n-pentyl)-in- .dole, 800 parts of cyclohexanone, 74 parts of aluminum isopropoxide, and 2500 parts of toluene isheated at re- 'fiuxfor about35 minutes. 'This mixture is cooled, washed 4 distillation of the product at about -150/0.05 mm. Recrystallization from isopropanol affords pure 3-(2-oxon-pentyl)indole.

EXAMPLE 4 3- (Z-hydrazino-Z-n-propyl) ethylindole By substituting 3-(Z-oxo-mpentyDindole for 3-(2-oxopropyl)indole in the procedure described in Example 2, Y razino 2- -p py t ylindo s b ain d.

- EXAM E 5 3-(2-n-hexylhydrazino-Z-n-propyl)ethylindole By substituting 3.-(2-oxo-n-pentyl)indole and n-hexylhydrazine for 3-(2-oxopropyl)indole and hydrazine hydrate, respectively, in the process of Example 2; 3-(2-nhexylhydrazino-2-n-propyl)ethylindole is obtained.

What is claimed is:

1. A compound of the structural formula l p onlcnnrrmnm \N: l

wherein R and R are selected from the group consisting of hydrogen and lower alkyl radicals.

2. A compound of the structural formula wherein R and R are lower alkyl radicals. 3. A compound of the structural formula wherein R is a lower alkylradical;

4. 3-(2-hydrazino-2-methy1)'ethylindole.

References Cited in the file of this patent Thesing et a1.: Berichte, 'vol. 89' (1956), pp. 1195- 1203. 

1. A COMPOUND OF THE STRUCTURAL FORMULA 